The present invention relates to novel compounds and compositions, and methods of their use in the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain substituted tetrahydrofuran analogs of E series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage, and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which reduce either the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the flow of aqueous humor out of the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects, such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Moreover, some beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics may cause tachycardia, arrhythmia and hypertension. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.
Prostaglandins, which are metabolite derivatives of arachidonic acid, have recently been pursued for possible efficacy in lowering IOP. Arachidonic acid in the body is converted to prostaglandin G.sub.2, which is subsequently converted to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGE.sub.2 (formula I): ##STR1##
The relationship between EP receptor activation and IOP lowering effects is the subject of some debate. There are currently four recognized subtypes of the EP receptor: EP.sub.1, EP.sub.2, EP.sub.3, and EP.sub.4 (J. Lipid Mediators Cell Signaling, volume 14, pages 83-87 (1996)). It is known in the art that IOP may be lowered by ligands capable of EP.sub.2 receptor activation, such as PGE.sub.2 and certain of its synthetic analogs (Journal of Ocular Pharmacology, volume 4, number 1, pages 13-18 (1988); Journal of Ocular Pharmacology and Therapeutics, volume 11, number 3, pages 447-454 (1995)), or EP.sub.3 receptor activation (Journal of Lipid Mediators, volume 7, pages 545-553 (1993); Investigative Ophthalmology and Visual Science, volume 31, number 12, pages 2560-2567 (1990)). However, some of these molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing, including an initial increase in IOP, photophobia, and eye ache (see for example Journal of Ocular Pharmacology, volume 4, number 1, pages 13-18 (1988)).
A number of synthetic prostaglandins have been observed to lower IOP, but such compounds typically produce the aforementioned and other undesirable side effects in varying degrees, which greatly limit their clinical utility. Therefore, a need exists for the development of molecules that may activate the prostaglandin EP receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over endogenous prostaglandins, and methods of their use. Certain 9-keto-11-oxa prostaglandins are disclosed in UK Patent No. 1,539,364. That reference, however, does not disclose the compounds of the present invention, nor does it suggest that such compounds would have an improved therapeutic profile in the treatment of glaucoma and ocular hypertension.